On the morning before a recent surgical procedure I took the antibiotic levofloxacin, which my surgeon had prescribed to reduce the risk of infection. I took it at 6:15, had my usual breakfast, and by 6:45 I was on the can with the first of what turned out to be seven bouts of Montezuma’s revenge that day, without the pleasures of a trip to Mexico. I faked my way through my morning appointments and the first one of the afternoon, but by 1:30 I could hardly sit in my chair. I had to cancel the next six appointments and call my wife to pick me up. As alarming as all the water I was producing was the rapid loss of my ability to think about anything more complicated than lying down. It seemed as though, along with everything else, I had flushed by brain down the toilet.
The next day I’d recovered enough to complete the procedure, and my chart now registers my allergy to levofloxacin, and presumably all other flouroquinolones—my first drug allergy. This cathartic experience forced on me a stunning reminder of how much our brain relies on a functioning gut to do its most basic tasks: listen, remember, talk, write. I had plenty of time that week to think about the conversation going on between my gastrointestinal system and my central nervous system.
Most of that conversation runs up and down the many branches of the vagus nerve, the most interesting nerve in our bodies. Why? Because the vagus nerve has its roots in our brainstem and “wanders” to all organs in the body from the neck to the hips. The vagus nerve has been described as the “brain’s window into the body,” because it both receives signals about the state of each of our organs and it delivers signals that help regulate their functioning. Some branch of our vagus nerve is tending to our breathing, swallowing, digesting, defecating, heart pumping, infection fighting, sexual excitement, sneezing, sighing, and our drifting off to sleep.
When my gut fired up its allergic storm, alarm signals from my gut rattled the vagus nerve nuclei in my brainstem enough to trigger nausea that kept me from adding to the trouble down there. And it forced a fatigue severe enough to drive me to bed. At the same time, the allergic reaction itself—picture an angry rash of red bumps up and down the inner surface of my duodenum and colon—was dumping toxic cytokines into my blood stream that shut down for that day my usual brain activities. These are the same cytokines that wreak such havoc in larger numbers during COVID cytokine storms.
While listening to this conversation between my gastrointestinal and central nervous systems, I remembered a fascinating talk in 2016 by the neurosurgeon Kevin Tracey from the Feinstein Institute and Hofstra University in New York. I knew Tracey as the author of a trailblazing 2002 paper in Nature called “The Inflammatory Reflex,” [link] and I had spent a day with him and a small number of experts at the Cleveland Clinic in 2007 talking about depression and heart disease. He had worked out how the central nervous system and the immune system communicate, much of it through the mysterious vagus nerve networks.
By 2016 Tracey and his group had identified a large number of reflex arcs within the vagus nerve network that he planned to explore surgically for their roles in a range of conditions. For example, people with arrhythmias of the heart, like atrial fibrillation, likely have dysregulations in a specific set of vagus nerve circuits that are anatomically distinct from the circuits dysregulated in people with diverticulitis or diabetes. Tracey challenged us to imagine a time when we will be able to identify these dysregulated circuits and, with the help of vagus nerve stimulation targeting a specific circuit, reverse these disorders without disrupting the rest of the vagus nerve system. How’s that for personalized medicine?
More recently Tracey and his colleague Valentin Pavlov outlined the promises of a new field called “bioelectronic medicine” (link to https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098260/) to harness what we know about the electrical circuits in the body for the improvement of conditions as varied as diabetes, heart failure, blindness, paralysis, hypertension, depression, and obesity. Think of bioelectronic medicine as a frontier, one as potent as the pharmacology frontier when it arrived in the 20th century, after eons of natural herbs as our only medications. Modern pharmacology introduced the possibility of treatments that adjusted a specific set of chemical receptors to change a specific pathologic process such as an infection or a seizure. This approach has required exposing the whole body to the medication in order to deliver it to the intended site, the infected lung or the seizing brain. Medication side effects have been unavoidable and too often the limiting factor in the medication’s usefulness.
Bioelectronic medicine promises treatments that are confined to the problem area. The early forms of bioelectronic treatments that we already know—ECT, heart pacemakers, transcranial magnetic stimulation, spinal cord stimulation, and vagus nerve stimulation—represent relatively crude interventions along the range of possible neuromodulators that currently treat depression, heart disease, back pain, and epilepsy. The promising advantage of newer bioelectronic treatments is the possibility of delivering for a wide range of illnesses interventions that are confined to the neural circuits of the person’s problem organ or area of concern, without exposing the rest of the body to the effects of the treatment. Side effects should be much less of a barrier to effective treatment.
I’m keen on these innovations in bioelectronic medicine because they hold great potential for influencing the course of stress-related disorders. The common denominator across all stress-related disorders is a pattern of autonomic imbalance, or too much stimulation and not enough relaxation. In physiologic terms that translates into too much adrenalin or sympathetic nerve activity and not enough parasympathetic or vagus nerve activity. Careful use of bioelectronic treatments could help restore balance to a dysregulated stress response system.
And our public health burden weighs in heavily with stress-related disorders. Consider that at least 16% of all children in the US are exposed to toxic stress [link to https://www.cdc.gov/violenceprevention/aces/fastfact.html ], rich and poor alike. Add all those adults with multiple chronic illnesses, which are themselves stressors made worse by other forms of toxic stress. Then add all those who live under the persistent threats of unemployment, poverty, crime, harassment, and discrimination. Toxic stress and stress-related disorders add up to a greater problem than diabetes, possibly as big as obesity, which now afflicts one in three US adults [link to https://www.cdc.gov/obesity/data/prevalence-maps.html ].
This may sound like welcoming science fiction into your doctor’s office, but bioelectronic medicine, when it helps us modulate specific neural circuits in our stress response systems, will offer more targeted personalized treatment plans for stress-related disorders than we have ever seen. We have lots to learn before then about what makes for safe and effective treatment with these new neuromodulators, but my gut tells me that bioelectronic medicine will soon change the face of modern medicine for the better.